TNF-α/IFN-γ-induced iNOS expression increased by prostaglandin E2 in rat primary astrocytes via EP2-evoked cAMP/PKA and intracellular calcium signaling

Han Yun Hsiao, Oi Tong Mak, Chung Shi Yang, Yu Peng Liu, Kuan Ming Fang, Shun-Fen Tzeng

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Astrocytes, the most abundant glia in the central nervous system (CNS), produce a large amount of prostaglandin E2 (PGE2) in response to proinflammatory mediators after CNS injury. However, it is unclear whether PGE2 has a regulatory role in astrocytic activity under the inflamed condition. In the present work, we showed that PGE2 increased inducible nitric oxide synthase (iNOS) production by tumor necrosis factor-α and interferon-γ (T/I) in astrocytes. Pharmacological and RNA interference approaches further indicated the involvement of the receptor EP2 in PGE2-induced iNOS upregulation in T/I-treated astrocytes. Quantitative real-time polymerase chain reaction and gel mobility shift assays also demonstrated that PGE2 increased iNOS transcription through EP2-induced cAMP/protein kinase A (PKA)-dependent pathway. Consistently, the effect of EP2 was significantly attenuated by the PKA inhibitor KT-5720 and partially suppressed by the inhibitor (SB203580) of p38 mitogen-activated protein kinase (p38MAPK), which serves as one of the downstream components of the PKA-dependent pathway. Interestingly, EP2-mediated PKA signaling appeared to increase intracellular Ca2+ release through inositol triphosphate (IP3) receptor activation, which might in turn stimulate protein kinase C (PKC) activation to promote iNOS production in T/I-primed astrocytes. By analyzing the expression of astrocytic glial fibrillary acidic protein (GFAP), we found that PGE2 alone only triggered the EP2-induced cAMP/PKA/p38MAPK signaling pathway in astrocytes. Collectively, PGE2 may enhance T/I-induced astrocytic activation by augmenting iNOS/NO production through EP2-mediated cross-talk between cAMP/PKA and IP3/Ca2+ signaling pathways.

Original languageEnglish
Pages (from-to)214-223
Number of pages10
JournalGLIA
Volume55
Issue number2
DOIs
Publication statusPublished - 2007 Jan 15

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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